This proposal is a continuing study of Beta mechanism and selectivity of action of pyrimidine nucleoside derivatives that have chemotherapeutic activity. Two specific projects are of current interest: 1. Metabolism and Effects of 2'-fluoro-5-iodo-1-Beta-D-arabinofuranosyl cytosine (FIAC) in Human and Murine leukemic cells. A new potent antiherpesvirus compound, FIAC, inhibits the growth of human cell lines in culture (ED 50 less than 0.1 micro mole) but is less inhibitory to P815 murine leukemic cells. It is proposed that FIAC be studied in human leukemic and murine leukemic cells to explore the biochemical basis for the selectivity of its cytotoxic effects. Bone marrow and/or peripheral leukemic cells from patients with different types of leukemia, established human cell lines, and p815 cells sensitive and resistant to arabinosylcytosine (ara-C) will be used. To be studied are 1) the effect of FIAC on metabolism of tritiated natural nucleosides; 2) the metabolism of (2-14C) FIAC in different leukemic cells, i.e., deamination, phosphorylation and incorporation into DNA and/or RNA and the identity of the labeled moiety(ies) in nucleotides and nucleic acids; 3) the effects of natural nucleosides on the metabolism of (2-14C) FIAC; and 4) the rates of transport and metabolism of (2-14C) FIAC by leukemic cells. 2. Transport and Metabolism of (2-14C) Pseudoisocytidine (14C psi IC). Psi IC is a new C-nucleoside that is effective against P815 cells and its subline resistant to ara-C. Preclinical studies in this laboratory showed an accumulation of 14C-psiIC by rat liver and Phase I clinical trials manifested hepatotoxicity. In this project, isolated hepatic cells of rats and P815 Cells sensitive and resistant to psiIC will be used to study the transport of (14C) psiIc by a double syringe rapid mixing apparatus and an oil-layer rapid separating technique.